1-hydroxycortisone, 1-hydroxyhydrocortisone and esters thereof



United States Patent O l-HYDROXYCORTISONE, l-HYDROXYHYDRO- CORTISONE ANDESTERS THEREOF Hershel L. Herzog, Mountain View, N. J., assignor toSchering Corporation, Bloomfield," N. J., a corporation of New Jersey NoDrawing. Application January 19, 1955, Serial No. 482,890

11 Claims. (Cl. 260-39145 CHgOAC wherein X represents OH or =0, Yrepresents OH or OAc and Ac represents a lower alkanoic acid radical.

The following is a typical sequence of reactions by which the newcompounds of the invention may be made:

CHzOAc CHzOAc X I X Q at.

CHzOAG l---on m 0 O: O i

7 III IV ice VII

wherein X represents OH or =0 and Ac represents a lower alkanoic acidradical.

For example, in converting 1-pregnene-1a,21-diol- 3,11,20-trioneZI-acetate (Mattox and Kendall, J. B. C., 188, 287 (1957)) to4-pregnene-1,17a,21-trio1-3,11,20- trione and the corresponding1,21-diacetate, the starting material (I) is expoxidized by means of oneof the well known expoxidizers such as perbenzoic acid, monoperphthalicacid, peracetic acid, etc. Preferably perbenzoic acid or monoperphthalicacid in an inert medium such as chloroform or methylene chloride is usedin this step. The product of epoxidation (II) is then treated with ananhydrous hydrohalic acid such as hydrogen bromide in chloroform,hydrogen iodide in glacial acetic acid, etc. The resultant halohydrin(III), preferably the iodohydrin, is then dehalogenated with Raneynickel in acetic acid, or with hydrogen and palladium-on-calciumcarbonate catalyst to pregnane-l,17a,21-trio1-3,11,20-trione (IV).Compound IV is acylated with a lower alkanoic acid anhydride or acidchloride, such as acetic anhydride, in pyridine solution to yield V.Alternatively, compound V may be prepared by reversing the order of thelast two steps. Bromination and dehydrobromination of V afiords thedesired 4-pregnene-l,17a,21-triol-3,11,20-trione 1,21- diacetate. Thebromination is preferably conducted with bromine, in the presence ofsodium acetate to control the acidity. The dehydrobromination is mostconveniently accomplished with the aid of semicarbazide. The resultingsemi-carbazone is converted to VII by the action of pyruvic acid.

In similar fashion IV is convertible to 4-pregnene-1,17u,21-triol-3,11,20-trione 21-acetate (VIII) by omitting the acylationstep. Bromination in the presence of sodium acetate followed by the samedehydrobrornination procedure efiects the desired transformation.

The corresponding lle-hydroxy-compounds are prepared in the same waystarting from l-pregnene-llfl; 17 a,21-triol-3,20-dione 21-acetate.

The particular importance of VII, VIII and the relatedllfl-hydroxy-compounds is that upon treatment with an acid or base suchas alumina, Triton B, etc., the oxygenated substitutent at liseliminated readily aifording the powerful antiarthritic, A -diene-3-onecompounds. Furthermore, the l-oxygenated derivatives possessadrenocortical properties and are useful in the therapy of arthritis andother afiiictions known to respond to the adrenocortical hormones.

EXAMPLES 1,2 0xid0pregnane-17a,21-di0l-3,1l,20-tri0ne 21-acetate.-To asolution of 0.4 g. of 1-pregnene-l7a,21-diol- 3,11,20-trione 21-acetatein ml. of chloroform at 5 C. is added 0.14 g. of perbenzoic acid in 25ml. of chloroform. The resulting mixture is allowed to stand at 5 --C.overnight and is then washed with dilute aqueous sodium bicarbonate. Thechloroform solution is then dried and concentrated in vacuo. The residueis crystal- 3 lized from acetone-hexane affording crystalline1,2-oxidopregnane-17u,21-diol-3,11,20-trione 21-acetate.

Z-bromoprcgnane-L]7a,2l-tri0l-3,l1,20-tri0ne 2l-acetate.T a solution of0.42 g. of l,2-oxidopregnane 17ct,21-diol-3,11,20-trione ill-acetate in100 ml. of chloroform at C. is added 0.08 g. of anhydrous hydrogenbromide dissolved in 100 ml. of chloroform. The mixture is allowed tostand at 5 C. for one hour and is then concentrated in vacuo. Theresidue is crystallized from methylene chloride-hexane affordingcrystalline 2-bromopregnanel,l7a,2l-triol-3,11,20-trione 2l-acetate.

Pregame-1,]7a,2]-Zriol-3,]1,20-rri0ne 21 acetate.A solution of i g. ofZ-bromopregnane-l,17a,21-triol-3,11, 20trione Zl-acetate in l00 ml. ofmethanol is shaken with g. of 10% palladium-on-calcium carbonatecatalyst in an atmosphere of hydrogen at atmospheric pressure. After oneequivalent of hydrogen has been taken up (several hours shaking), thecatalyst is filtered from the solution and the filtrate is concentratedin vacuo to a solid residue, prcgnane-1,17a,2l-triol-3,11.20-trioneZl-acetatc. Pregnrme-I, I7c,2l-!/'{0l-3,I1,20-iri0ne 1,2I-diacetare. Thecrude product from the preceding experiment is dissolved in a mixture of0.5 ml. of acetic anhydride and 5 ml. of pyridine. The reaction isallowed to proceed overnight and then the mixture is diluted withice-water. The resulting precipitate is filtered and recrystallized frommethylene chloride-hexane allot-ding crystallinepregnancl,l7a.2l-triol-3,l1,20-trione 1,21-diacetate.

4-bromoprcgmmcJ,17a,21!ri0l 3,11,20 trione 1,21- diacc!ate.--To asolution of 0.46 g. of pregnane-1,17a,2ltrio-l-3,l1,20-trionel,2l-diacetate in 50 ml. of glacial acetic acid is added 0.5 ml. of 0.28N hydrogen bromide in acetic acid. Then there is added dropwise withgood agitation a solution containing 0.16 g. of bromine, 0.08 g. ofsodium acetate and ml. of glacial acetic acid at such a rate that eachdrop has the opportunity to react before another is added. When additionis complete the reaction mixture is diluted with five volumes of waterand the precipitated 4-hromopregnane-l,17u,21-triol-3,l1,20-trione l,Zl-tliacetate is collected by filtration.

4-pregneize-J,17a,2]-tri0l-3,]1,20 trione 1,21 diocetme.T0 a solution of0.54 g. of 4-bromopregnane-L17a, 2l-triol-3,l,2-trione 1,2l-diacetate in50 ml. of glacial acetic acid is added, under an atmosphere of carbondioxide, a solution containing 0.25 g. of semicaroazide hydrochloride,150 mg. of anhydrous sodium acetate, .10 ml. or water and 10 ml. ofglacial acetic acid. The mixture is agitated for ten minutes and thereis then added ml. of 1 N sodium acetate in glacial acetic acid.Agitation is continued for i0 minutes longer, 2 ml. of pyru- Vic acid isadded and the mixture is refluxed for ten minutes. The cooled solutionis diluted with water and extracted. with methylene chloride. Theextracts are washed free of acid with water and the solution is driedover magnesium sulfate. Concentration of t.e dry solution and additionof hexane induces crystallization of4-pregnene-l,l7a,2l-triol-3,l1,20-trione 1,21-diacetate.

Pregnane-l,l7ix,2l-triel-3,ll,20-trione Zl-acetate may be brominated anddehydrobromiuated by the procedure described in the previous twoexamples, afiording crystalline 4-pregnene-l,l7a,2l-triol-3,11,20-trioneZl-acetate.

LZ-OxidOpregrIarwJI-tt,17a,2]-tri0l3,20-di0ne 2Iacemte.To a solution 0.4g. of l-pregnene-l1B,17a,2ltriol-3,20-dione Zl-acente in 100 ml. ofchloroform at 5 C. is added 034 g. of perhenzoic acid in ml. ofchloroform. The resulting mixture is allowed to stand at 5 C. overnightand is then washed with dilute aqueous sodium bicarbonate. Thechloroform solution is then dried and concentrated in vacuo. The residueis crystallized from acetone ne ane affording crystalline1,2-oxidopregnane-l15.17a,2l-triol-iZO-dione Zl-acetate.

2-12romopregzzmm-I,1Ifl,]7a,21-tetr0l 3,20 dione 21- acetate.To asolution of 0.42 g. of 1,2ioxidopregnane-ll[9,17u,21-triol-3,20-dione21-acetate in 100 ml. of

chloroform at 5 C. is added 0.08 g. of anhydrous hydrogen bromidedissolved in 100 ml. of chloroform. The mixture is allowed to stand at 5C. for one hour and is then concentrated in vacuo. The residue iscrystallized from methylene chloride-hexane affording crystalline 2-bromopregnanel ,1 1B,17a,21-tetrol-3,20-dione 2l-acetate.

Pregnane-I ,1 l-flJ 7a,21-tetr0l-3,20-di0ne 21-acetate.- A solution of 1g. of 2-bromopregnane-1,11-,B,17-a,21- tetrol-3,20-dione ZI-acetate in100 ml. of methanol is shaken with 10 g. of. 10% palladium-on-calciumcarbonate catalyst in an atmosphere of hydrogen at atmospheric pressure.After one equivalent of hydrogen has been taken up (several hoursshaking), the catalyst is filtered from the solution and the filtrate isconcentrated in vacuo to a solid residue of pregnane-l,ll-B,l7a,21-tctroLLZO-dione ZI-acetate.

Prcgnmze-I,11-B,I7-a,2l-l'etr0l-3,20 dione 1,2I-diacetate.The crudeproduct from the preceding example is dissolved in a mixture of 0.5 ml.of acetic anhydride and 5 ml. of pyridine. The reaction is allowed toproceed overnight and then the mixture is diluted with ice-water. Theresulting precipitate is filtered and recrystallized from methylenechloride-hexane affording crystallinepregnancl,11e,l7a,2l-tetrol-3,20-dione 1,2l-diacetate.

4-br0m0pregrsm1c-1,]Ifi,l7oc,21tefr0l-3,2O dione 1,21- diacetme.T0 asolution of 0.46 g. of pregnane1,1lfi, 17a,21-tetrol-3,20-dione1,21-diacetate in ml. of glacial acetic acid is added 0.5 ml. of 0.28 Nhydrogen bromide in acetic acid. Then there is added dropwise with goodagitation a solution containing 0.16 g. of bromine, 0.08 g. of sodiumacetate and 15 ml. of glacial acetic acid at such a rate that each drophas the opportunity to react before another is added. When addition iscomplete the reaction mixture is diluted with five volumes of Water andthe precipitated 4--bromopregnane-1,115,17a, 2l-tetrol-3,20-dione1,21-diacetate is collected by filtration.

4-preg.'tenc-1,l]fl,]711,2I-tetr0I-3,20-di0ne 1,21 diacemtc.To asolution of 0.54 g. of 4-bromopreguane-Ll1fl, 17m,21-tetrol-3,20-dione1,2l-diacetate in 50 ml. of glacial acetic acid is added, under anatmosphere of carbon dioxide, 21 solution containing 0.25 g. ofsemicarbazide hydrochloride, 180 mg. of anhydrous sodium acetate, 10 ml.of Water and 10 ml. of glacial acetic acid. The mixture is agitated forten minutes and there is then added 20 ml. of l N sodium acetate inglacial acetic acid. Agitation is continued for 10 minutes longer, 2 ml.of pyruvic acid is added and the mixture is refluxed for ten mintues.The cooled solution is diluted with Water and extracted with methylenechloride. The extracts are washed free of acid with water and thesolution is dried over magnesium sulfate. Concentration of the drysolution and addition of hexane induces crystallization of4-pregnene-l,11;3, l7-a,2 l-tetrol-3,20-dione 1,21-diacetate.

Pregnane-1,11B,]7a,2l-tetrol-3,20-dione ZI-acetate may be brominated anddehydrobrominated by the procedure described in the previous twoexamples, affording crystalline4-pregnene-1,l1B,l7a,2l-tetrol-3,20-dione Ill-acetate.

Elimination of the I-hydroxyl group with alumina.A solution of 0.1 g. of4-pregnene-l,llfi,l7u,2l-tetrol-3,20 dione 2l-acetate in ml. ofchloroform is passed over an activated alumina (30 g. or 100200 mesh)column and the column is then Washed with methanol. The combined.eluates are concentrated and the residue, which crystallizes fromacetone, is identical in all respects withl,4-pregnadiene-11B,17a,2l-triol-3,20-dione 21 -acetate.

A solution of 0.1 g. of 4-pregnene-l,l7a,2l-triol-3,ll,- 20-trione21-acetate in 100 ml. of chloroform is passed over an activated alumina(30 g. of 100200 mesh) column and the column is then washed withmethanol. The combined eluates are concentrated and the residue, whichcrystallizes from acetone, is identical in all respects withl,4-pregnadiene470:,2l-di0l-3,11,20-trione 2l-acetate.

I claim: 1. Compounds of the formula CHQOAC C=O -OH OHzOAc successivelybrominating in the 4-position and debrominating a compound of theformula 6 7. The method of making l-oxygenated steroid compounds of theformula wherein X is selected from and :0, Y is selected from OH andOAc, and Ac represents a lower alkanoic acid radical which comprisesdehalogenating a compound of the formula OHzOAc wherein Hal is selectedfrom bromine and iodine, and successively brominating in the 4-positionand debrominating the resulting compound.

8. Compounds as defined in claim 1 wherein X is C HzOAc and Y is OAc. t9. Compounds as defined in claim 1 wherein X is =0 and Y is OAc.

10. Compounds as defined in claim 1 wherein X is 11 and Y is OH.

11. Compounds as defined in claim 1 wherein X is =0 and Y is OH.

References Cited in the file of this patent UNITED STATES PATENTS2,380,483 Wagner July 31, 1945 2,673,867 Spero Mar. 30, 1954 2,715,640Ralls Aug. 16, 1955 FOREIGN PATENTS 1,056,878 France Oct. 28, 1953

1. COMPOUNDS OF THE FORMULA